The broad and long-term objective of this research project is to develop effective neuromodulation methods for atrial fibrillation (AF) control. It is known that the autonomic nervous system (ANS) is important in controlling both heart rhythm and cardiac contractility. In a previous funding period, we successfully developed methods to record autonomic nerve activities in ambulatory dogs, and documented their importance in cardiac arrhythmogenesis. We1, 26 also discovered that vagal nerve stimulation (VNS) can effectively induce left stellate ganglion (LSG) remodeling and suppress the stellate ganglion nerve activity (SGNA). A possible therapeutic mechanism is that vagal nerves contain significant amount of sympathetic nerve fibers. Passive activation of these sympathetic nerve fibers may retrogradely activate LSG at high rate and cause excitotoxicity. Death of ganglion cells then lead to reduced sympathetic outflow. In addition to LSG damage, we found that the damage may extend to the right stellate ganglion (RSG) and the brain stem. Therefore, to better understand the mechanisms of VNS, we will need to study the latter nerve structures and other autonomic nerve structures that innervate the heart. If excitotoxicity underlies the therapeutic effects of cervical VNS, then it follows that stimulating any peripheral sympathetic nerve fibers that originate from the stellate ganglia (SG) should also help control AF through SG damage. In dogs, the postganglionic sympathetic nerve fibers of neck and thorax came primarily from the SG. Our preliminary studies showed that subcutaneous nerve activity (SCNA) and superficial skin sympathetic nerve activity (SKNA) closely correlates with the SGNA. Subcutaneous nerve stimulation (SCNS) from 3 different sites can damage SG and reduce SGNA. These findings suggest an exciting possibility that electrical stimulation of the skin may reduce SGNA and suppress cardiac tachyarrhythmias. In addition to excitotoxicity, transneuronal (or trans-synaptic) degeneration is also a well- described phenomenon in the central and peripheral nervous system that may remain active both at the level of the insult and in the remote brain structures up to 1 year post-trauma. Transneuronal labeling of central nervous system neurons have been documented after pseudorabies virus injection into the SG. Because of the synaptic connections, SG damage may result in the changes of the CNS through transneuronal degeneration. Similarly, catheter ablation of the renal sympathetic nerves may also cause extensive changes of CNS through the same mechanism. We have obtained preliminary data that suggest brain stem damage after VNS and renal denervation (RD). If proven true, these new findings will provide significant new insights into the mechanisms as well as potential side effects of neuromodulation. The specific aims include: (1) Estimating sympathetic tone by SCNA and SKNA. (2) Mechanisms of antiarrhythmic action of cervical vagal nerve stimulation (VNS). (3) Effects of subcutaneous nerve stimulation on the brain stem and SG. (4) Effects of renal denervation (RD) on the brain stem and SG.